Summary of work: The pathogenesis of degenerative diseases of aging involve the loss of important functional cell types . Apoptosis is a form of programmed cell death that is responsible for the elimination of many cell types during development. We are carrying out studies to determine the importance of apoptosis in the biology of the chondrocyte. Over the past year we have been successful in applying an in situ procedure for the detection of apoptotic cells to cartilage. We have made the exciting discovery that chondrocytes in the articular cartilage of mature animals are undergoing apoptosis and that the number of apoptotic cells increases with age. This finding supports the concept that loss of chondrocytes by programmed cell death may contribute to the development of age-associated degenerative cartilage disease. This work will be extended to examine the occurrence of apoptosis in the articular cartilage of transgenic and spontaneous animal models of cartilage disease. In addition, we will determine if apopototic chondrocytes are present in human articular cartilage. In parallel studies we are studying the regulation of apoptosis in vitro in primary articular chondrocytes and cell lines. Here we have determined that chondrocytes express Bcl-2 (a protein that prevents apoptosis) and that the level of Bcl-2 is down-regulated by conditions that induce apotosis such as serum withdrawal. These studies will allow us to develop strategies to regulate chondrocyte apoptosis and intervene in the loss of chondrocytes that occurs during aging.